Large stokes shift fluorescent dyes based on a highly substituted terephthalic acid core

Article abstract of DOI:10.1021/ol300038e

The synthesis of dyes based on a highly substituted terephthalic acid core is described, starting from readily available 2,5-dihydroxy-terephthalic acid diethyl ester. The dyes are highly colored, soluble in organic solvents and reasonably fluorescent in

Full text of DOI:10.1021/ol300038e

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1374–1377
Large Stokes Shift Fluorescent Dyes
Based on a Highly Substituted
Terephthalic Acid Core
Andrew C. Benniston,*,† Thomas P. L. Winstanley,† Helge Lemmetyinen,‡
Nikolai V. Tkachenko,‡ Ross W. Harrington,§ and Corinne Wills
Molecular Photonics Laboratory, School of Chemistry, Newcastle University,
Newcastle upon Tyne, NE1 7RU, U.K., Department of Chemistry and Bioengineering,
Tampere University of Technology, P.O. Box 541, 33101 Finland, and Crystallography
Laboratory, NMR Analytical Laboratory, School of Chemistry, Newcastle University,
Newcastle upon Tyne, NE1 7RU, U.K.
a.c.benniston@ncl.ac.uk
Received January 9, 2012
ABSTRACT
The synthesis of dyes based on a highly substituted terephthalic acid core is described, starting from readily available 2,5-dihydroxy-terephthalic
acid diethyl ester. The dyes are highly colored, soluble in organic solvents and reasonably fluorescent in solution and in the solid state. The
maxima for absorption and emission are around 402 and 502 nm, respectively. The fluorophores are readily cyclized to generate compounds
which comprise the basic 6,13-dihydroxy-chromeno[2,3-b]xanthene-7,14-dione unit. These new derivatives are nonfluorescent.
Fluorescence is one of the most powerful tools used in
diagnostics (e.g., ion sensing), because of its extreme
sensitivity, low concentration of dye required, and ease in
accumulating a good signal-to-noise.1 A rather pertinent
example is in the medical field where fluorophores are
routinely used in cell imaging, analyte recognition2 and the
detection of radicals.3 However, autofluorescence (i.e., back-
ground noise from other chromophores) can be a prob-
lem, especially if there is considerable overlap of fluores-
cence signals from multiple chromophores.4 A number of
solutions to the problem have been developed covering,
for example, the use of time-gated spectroscopy5 and
lanthanide millisecond emitters,6 delayed fluorescence,7
† Molecular Photonics Laboratory, Newcastle University.
‡ Tampere University of Technology.
§ Crystallography Laboratory, Newcastle University.
NMR Analytical Laboratory, Newcastle University.
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4716–4719.
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J. Am. Chem. Soc. 2005, 127, 16652–16659.
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11, 9560–9572.
r
10.1021/ol300038e
Published on Web 03/01/2012
2012 American Chemical Society

employment of long-wavelength absorbing/near I.R.
emitters8 and large Stokes’ shift dyes.9 Certainly this latter
solution is promising if a suitable dye can be identified
where the structures of the emissive and ground state are
very different. Molecular systems based on coumarin are
known to be large Stokes’ shift emitters.10 In a quest to
develop new fluorescent materials we turned our attention
to dyes prepared some time back as basic pigments. The
intention was to identify a simple dye framework, which
could be prepared in a few steps, in reasonable amounts,
and from easily sourced starting materials. Ready functio-
nalization to tune the electronic properties of the dye
was an added proviso. The 6,13-dihydroxy-chromeno-
[2,3-b]xanthene-7,14-dione unit was developed a while
ago as a pigment, and it is interesting that the dye turns
from red to darkblue in very concentrated acid.11 No other
properties of the compound were reported, especially any
absorption and fluorescence spectra. The basic dye struc-
ture and appealing color change led us to believe that other
derivativeswould beworth pursuing. Here, the synthesisof
several derivatives are described, focusing especially on the
precursor compounds prior to final cyclization, based on a
highly substituted terephthalic acid core. These com-
pounds turn out to be highly fluorescent in solution and
display large Stokes’ shifts, plus they are strongly emissive
in the crystalline state.
Preparation of the dyes is shown in Scheme 1 starting
from the commercially available 2,5-dihydroxy-terephthalic
acid diethyl ester, and using procedures adapted from
published work by Liebermann et al.11 The reaction of
liquid bromine with the ester in the solid state produced
after work up and purification the quinone derivative 1 in a
95% yield. From this derivative the different aryloxy groups
were introduced using the appropriate alcohol and reflux in
pyridine and acetone. The percentage yields were all reason-
able ranging from 66% for 2b to 96% for 2a. The reduction
of the quinone derivatives 2 to form 3 proceeded well by
reaction in acetic acid with zinc metal and sonication. At this
stage it was noticed that the compounds were highly
fluorescent in the crystalline state and as amorphous pow-
ders. Instead of taking all the compounds through the next
three stages only two were selected to test conditions and to
optimize yields. Base hydrolysis of compound 3a and 3b
with KOH in ethanol afforded the carboxylic acids 4a and
4b, respectively. The reaction of 4a with benzoyl chloride in
the presence of conc. H2SO4 gave the cyclized product 5a as
a yellow solid in good yield. The removal of the benzoyl group
by aniline reflux afforded the 6,13-dihydroxy-chromeno-
[2,3-b]xanthene-7,14-dione derivatives 6a as a red solid.
The final compound was sparingly soluble in organic
solvents such as dichloromethane and chloroform. It should
be noted that the derivative without the tert-butyl groups is
totally insoluble in common organic solvents. Dissolving the
compounds in conc. H2SO4 produced a deep blue solution as
reported previously, which disappeared as the acid was
diluted very carefully with water. The red to blue color change
does not occur in weaker acids such as HCl and HNO3.
We undertook a very detailed analytical study for many
of the compounds shown in Scheme 1, aware that very
limited structural characterization was performed pre-
viously. In particular, many of the derivatives could be
crystallized and their molecular structures determined by
single-crystal X-ray analysis. Structures determined for 1,
2a-e, 3a-e, are all collected in the Supporting Information
(SI). An especially interesting case is for compound 3a
containing the two bulky tert-butyl groups. Analysis of the
1H NMR spectrum for compound 3a in a range of solvents
(e.g., CDCl3, d4-MeOH) revealed the presence of two dif-
ferent conformations in solution at room temperature.
This was most obvious for the two methylene groups of
the ester, which are split into two sets of complex multi-
plets. Contamination of the sample with the quinone form
is ruled out by comparison of the spectrum with that
collected on 2a in the same solvent. Several conformations
are possible for 3a depending on the relative orientation of
the aryl groups and the H-bonding site at the ester (Scheme 2).
There exists pathways to interconvert the conformations.
Perhaps worth noting is the difference in point group
symmetry between the syn and anti arrangements. For
A1 and A3 the point group is Ci whereas for S1 and S3 the
point group is C2. The point group for the in-between
conformations A2 and S2 is C1.
Scheme 1. Synthetic Procedures Used in the Preparation of a
6,13-Dihydroxy-chromeno[2,3-b]xanthene-7,14-dione Unit
(6) Bunzli, J.-C. G. Chem. Rev. 2010, 110, 2729–2755.
(7) Benniston, A. C.; Harriman, A.; Howell, S. L.; Sams, C. A.; Zhi,
Y.-G. Chem.;Eur. J. 2007, 13, 4665–4674.
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25, 289–292.
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J. Am. Chem. Soc. 2005, 127, 4170–4171. (b) Areneda, J. F.; Piers, W. E.;
Heyne, B.; McDonald, R. Angew. Chem., Int. Ed. 2011, 50, 12214–
12217.
(10) Signore, G.; Nifosi, R.; Albertazzi, L.; Storti, B.; Bizzarri, R.
J. Am. Chem. Soc. 2010, 132, 1276–1288.
(11) Liebermann, H.; Lewin, G.; Gruhn, A.; Gottesmann, E.; Schonda,
K.; Lisser, D. Chem. Ber 1934, 156–179.
Org. Lett., Vol. 14, No. 6, 2012
1375

Scheme 2. Possible Conformations for 3a Depending on the
‘Up-Up’ (Syn) and ‘Up-Down’ (Anti) Arrangement of the Two Aryl
Groups and the Site for Intramolecular H-Bonding to the Estera
a The tert-butyl groups are omitted for clarity, and the symmetry
operations are shown (S2 = inversion center).
Figure 1. Selected variable temperature 1H NMR spectra recorded
for 3a in d10-o-xylene highlighting the methylene protons.
Variable temperature (VT) NMR spectra for 3a in d10-o-
xylene were recorded to see if coalescence of the two
methylene multiplets occurred at high temperatures. Se-
lectedVT 1H NMR spectra recorded over 180 K are shown
in Figure 1. As the temperature is increased there is a clear
downfield shift, and at around 333 K there is a loss in
resolution for the two resonances. As the temperature is
increased further coalescence for the methylene protons
takes place at around 393 K. Least-squares fitting of the
rates for exchange at each temperature to an Arrhenius
model afforded an activation energy of 60 kJ molÀ1 (see SI).
The inequivalence of the methylene protons and hence
the complexity of the multiplets can be explained by the
lack of a symmetry plane relating Ha toHb and likewise Ha’
to Hb’. The bulky tert-butyl group restricts rotation of the
phenyl ring and so this group is locked on one or the other
sides of the putative plane, causing Ha/a’ and Hb/b’ to lie in
different environments. Thus, for each conformer a sixteen
line spectrum should be observed (i.e., two doublets of
quartets). This is not quite seen because of overlapping
peaks, but a simulation is remarkably similar to the
observed spectrum.
Figure 2. Single-crystal X-ray crystallographically determined
molecular structure for 3a.
Recognizing that the X-ray determined structure for 3a
may not necessarily be the true energy-minimized geome-
try, we undertook a preliminary computational molecular
modeling study in the gas phase. In the first instance, the
structure was minimized using a simple MM2 calculation,
and the geometry was forced into either the anti or syn
conformation. The two structures were then used to seed a
DFT calculation using B3LYP and the 6-311G basis set
using Gaussian 03.12 We were able to identify at least three
The X-ray determined molecular structure for 3a is
shown in Figure 2. It is evident that the two aryl groups
are disposed in the antiarrangement, and the intramolec-
ular alcohol hydrogen bonds are associated with the car-
bonyl groups of the ester functionality (i.e., A3, Scheme 2).
The ethyl groups for both esters are preorganized toward
the aryl rings. The hydrogen of the ester methyl group
appears to point toward the centroid of the aryl group
(12) Frisch, M. J.;Trucks, G. W.;Schlegel, H. B.;Scuseria, G. E.;Robb,
M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.;
Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03;
Gaussian, Inc.: Wallingford, CT, 2004.
˚
(H-aryl distance = 3.02 A). The bulky tert-butyl groups
serve the purpose of keeping the molecular units of 3a well
separated in the crystal lattice. The crystal packing dia-
gram (see SI) reveals that the terephthalate groups do not
appear to stack, and the centroid to centroid distance is
˚
7.6 A. The fact that the asymmeric units are well separated
is probably one reason for the observed fluorescence from
crystalline samples of 3a.
1376
Org. Lett., Vol. 14, No. 6, 2012

energy-minimized conformations reflecting a localized
minimum and the ground-state structures (see SI). Surpris-
ingly from the calculations it appears that the syn geometry
is ∼5 kJ molÀ1 more stable than the anti conformation.
For both structures the H-bonding motif is maintained at
the terephthalate site (see SI). The one tert-butyl group and
ethyl unit, plus the terephthlate hydroxyl and ring hydro-
gen, presumably impose steric constraints to free rotation
of each terminal aryl group. Interestingly, one minimized
structure to drop out of the calculation has the carbonyl
group of the ester disposed out of conjugation with the aryl
ring (see SI). This conformer is 21À25 kJ molÀ1 less stable
than the anti and syn forms and likely represents a struc-
ture somewhere along the potential energysurface between
the two. We expecta moredistinctpicturetoemergefor the
interconversion process from currently underway compre-
hensive conformer searching calculations. It is feasible that
tofacilitate the antiÀsyn conversion the ester group rotates
out of the plane to allow the O-aryl group to pass by
unhindered. Such a suggestion is not unreasonable
since preliminary molecular modeling calculations re-
veal that the energy barrier to rotation is extremely high
if the O-aryl group is basically rotated around its axis
(see SI).
absorption spectrum in overall appearance, and the quantum
yield of fluorescence (φFLU) is 0.19. What is very noticeable is
the large Stokes shift of 100 nm for 3a, which implies that the
structures of the emitting state and ground state are rather
different. Fluorescence decay, as measured by single-photon
counting, for 3a was strictly monoexponential with a life-
time (τS) of 3.3 ns. The rate for radiative decay (kRAD
=
φFLU/τS) of 5.8 Â 107 sÀ1 is in remarkably good agreement
(kRAD = 7.4 Â 107 sÀ1) with that calculated using the
modified StricklerÀBerg expression.13 As expected, the
rate of nonradiative decay for the first-excited singlet state
(kNR =1/τS À kRAD) of2.5Â 108 sÀ1 dominates. Alteration
in the aryl substituents had no obvious effect on the photo-
physical properties of the other compounds. In comparison,
the absorption maximum for the final fully ring-closed
compound 6a is red-shifted by some 95 nm (Figure 3), in
part because of the increased π-conjugation. However, no
discernible fluorescence is observed from the molecule in
fluid solution or the solid state. What is especially noticeable
is the fluorescent nature of the benzoyl protected precursor
5a and the accompanied shift in λABS to 402 nm. Once again
in the solid state the compound is fluorescent. It would
appear that the color for 6a is dependent on the dihydrox-
ybenzene motif. Intramolecular hydrogen bonding to form
two six-membered rings is very credible, as well as an
accompanied proton shift (single tautomerization). The
efficient first-excited state deactivation is likely linked to
the OH stretching vibration that serves to enhance non-
radiative decay as predicted by the energy-gap law.14
The intermediate compounds (3aÀ3e) are noticeably
fluorescent at room temperature in both the solid state and
in fluid solution (Figure 3). The solid state fluorescence is
We have demonstrated that highly substituted ter-
ephthalate-based compounds are highly blue emitters in
the solid state and in solution. Following three further basic
reactions the compounds are converted to the 6,13-dihy-
droxy-chromeno[2,3-b]xanthene-7,14-dione derivatives. Al-
though these compounds are highly red colored, they are
nonfluorescent. Reaction at the dihydroxy groups, however,
converts the color back to yellow and restores fluorescence.
We expect to utilize these two effects for the sensing of strong
alkylating agents associated with nerve agents.15
Acknowledgment. We thank Newcastle University for
financial support and the Engineering and Physical
Sciences Research Council (EPSRC) for purchase of the
diffractometer. The use of the EPSRC sponsored Mass
Spectrometry Service at Swansea is also appreciated.
Supporting Information Available. Experimental de-
tails, copies of NMR spectra for compounds, Arrhenius
plot, crystal packing diagram, computer calculated en-
ergy minimized structures, energy barrier calculation.
This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 3. (A) Ambient temperature absorption (black, 3a; gray,
6a) and fluorescence (red, 3a) spectra in dilute toluene. (B)
Pictures of solid samples of (left to right) 1, 3a, and 6a under
UV illumination (top) and normal light (bottom).
certainly absent for precursor samples such as 1 and 2aÀe.
As a typical example the ambient temperature absorp-
tion and fluorescence spectra for 3a in toluene are shown in
Figure 3. A relatively strong broad electronic absorption
band is located with a maximum at λABS = 402 nm and a
molar absorption coefficientεmax = 13 000MÀ1 cmÀ1. The
fluorescence profile located at λFLU = 502 nm mirrors the
(13) The modified expression is kRAD ≈ 3 Â 10À9 ν2εmaxΔν1/2, where
ν is the peak maximum (cmÀ1) and Δν1/2 is the peak width at half-height
(cmÀ1) for the fitted spectrum (see SI).
(14) Englman, R.; Jortner, J. Mol. Phys. 1970, 18, 145–164.
(15) Chen, W.; Elfeky, S. A.; Nonne, Y.; Male, L.; Ahmed, K.;
Amiable, C.; Axe, P.; Yamada, S.; James, T. D.; Bull, S. D.; Fossey,
J. S. Chem. Commun. 2011, 47, 253–255.
Org. Lett., Vol. 14, No. 6, 2012
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